Elmar Vilsmaier

Functionalized chloroenamines in aminocyclopropane synthesis - VI. Chlorotetrahydropyridines as a basis for the synthesis of 3-azabicyclo[3.1.0.]hexane derivatives☆

Abstract Enamines 8a-e could be chlorinated by equimolar amounts of N-chlorosuccinimide ( 9 ) generating monochloroenamines 10a-e ; 10a and 10d were isolated as pure substances. Two equivalents of 9 afforded the dichloroenamines 12a,c from 8a,c . Interaction of the chlorinated enamines 10a-e and 12a,c with cyanide gave morpholino-azabicyclohexane derivatives. 10a-d , thereby, led to exo-cyano-isomers lla-c ; 12a,c generated endo-cyano compounds 13a,c . In the case of the ethoxycarbonylated chloroenamine 10e a mixture of diastereomeric products 11e and 14e resulted from the analogous reaction. Reduction of 11a and 14e with lithium aluminum hydride produced a pair of diastereomeric triamines 15 and 16 . A tricyclic diazasystem 19 was formed from the reaction of cyanide with the carbamoylated chloroenamine 18 . Monochloroenamine 10a and dichloroenamine 12a showed a significant mutagenic behaviour in the Ames test.

Functionalized chloroenamines in aminocyclopropane synthesis - X. amino-azabicyclo[3.1.0]hexane diastereomers from chloroenamines and - organometallic compounds

Abstract Morpholino-chlorotetrahydro-N-methyl-pyridine 4 reacted with Grignard reagents 5 or diorganyl-magnesium compounds 6 to give a mixture of azabicyclo[3.1.0]hexane diastereomers 10 and 11 besides the monocyclic ketones 12. The latter were obtained as the sole products from chloroenamine 4 and dimethylzinc 7a or lithium dimethylcopper 8a. Organolithium compounds 9a,c or Grignard reagents 5a–c in the presence of TMEDA transferred 4 exclusively to endo-morpholino isomers 10. exo-Amines 11 could be obtained with high stereoselectivity from 4 via the N,O-acetal 13 and by the substitution of the methoxy moiety by a Grignard reagent 5. The stereochemical result of this substitution reaction can be explained by an intermediate complexation of the pyrrolidine N-atom in 13 by the Grignard reagent 5. An N-benzyl chloroenamine 14 instead of the N-methyl compound 4 showed a different reaction behavior with methylmagnesium bromide 5a leading only to endo-amine 15 which could be used as a precursor of the parent bicyclic system 16. The configurations of the bicyclic diamines 10, 11 and 15 were determined via 1H NMR data.

Functionalized chloroenamines in aminocyclopropane synthesis - viii. Amino-azabicyclo[3.1.0]hexane diastereomers from chloroenamines and - borohydride

Abstract Bicyclic endo-amines 6a,b could be prepared in a stereospecific way from the reaction of chloroenamines 1a,b and sodium borohydride and by deboranation of the primarily formed borane adducts 8. An X-ray structure analysis is given for 8a. In contrast to 1a,b, chloroenamine 1c and sodium borohydride preferentially produced an exo-amine 7c besides the endo-amine 6c (3 : 1). Subsequent LiAlH4-reduction of 7c allowed the synthesis of 7a - the diastereoisomer of 6a. Interaction of sodium borohydride with dichloroenamine 2a provided diamine 12 instead of an expected bicyclic exo-amine 10.

Functionalized chloroenamines in aminocyclopropane synthesis - XV. Synthesis of conformationally rigid analogues of [1,4′-bipiperidine]-4′-carboxamide - a common pharmacophoric group

Abstract 6-Piperidino-3-azabicyclo[3.1.0]hexane-6-carboxamide diastereomers 5 and 7 represent conformationally rigid analogues of the pharmacophoric group 1. Compounds 5 and 7 were synthesized with high stereoselectivity via chloroenamines 12a and 13b, respectively. Introduction of a 4-(4-fluorophenyl)-4-oxobutyl moiety in 5 and 7 led to derivatives 6 and 8 which correspond to rigid conformers of Pipamperone 2, a neuroleptic drug. An X-ray structure analysis was performed for compound 6; configuration and conformation of 5 – 8 were determined 1H NMR spectroscopically. 3′,5′-Cyclopipamperone diastereomers 6 and 8 showed different affinities to dopamine receptors D2L and D3.

Functionalized chloroenamines in aminocyclopropane synthesis. III: Synthesis and assignment of configuration of two isomeric morpholinobicyclo [3.1.0] hexane derivatives

Abstract Reaction of the acylated chloroenamine 7 with cyanide gave the endo-morpholino compound 11. The endo-morpholino configuration of 11 was established by subsequent ring closure reactions generating tricyclic derivatives 14, 16 and 17. LiAlH 4 reduction of 11 afforded aminoalcohol 12. The corresponding exo-morpholino isomer 20 could be obtained by LiAlH 4 reduction of exo-morpholino compound 19 which was accessible from N-tosylcarbamoylated chloroenamine 10 and cyanide. ΔGX values of 75.4–77.6 kJ/mol and 52.1 kJ/mol were determined for the morpholine dynamics in the two isomeric compounds 12 and 20, respectively. This demonstrates that 1 H NMR spectroscopic determination of the dynamics of morpholine allows an assignment of the configuration even in the case of twofold substituted morpholinobicyclo[n.1.0]alkane derivatives.

Functionalized chloroenamines in aminocyclopropane synthesis - XIV. Aminoannulated cyclopropanes - rigid building blocks for oligoamines

Abstract Sterically pure meander oligoamines 5 possessing bicyclo[3.1.0]hexyl moieties as rigid building blocks were synthesized from monoketal 9 via di(chloroenamine) 14, bicyclic diketones 16 and subsequent reductive amination of 16. Use of the same reactions and change of the sequence of the steps led to hexamine 6a, a diastereomer of 5a. Hexamine 7a, a third diastereomer of 5a, was obtained with definite stereochemistry by a multistep approach starting from monoketal 9, too. X-Ray analysis of hexamine 5a, determination of basicity and studies of conformation and of molecular flexibility gave an insight in structural properties of the new type of meander oligoamines 5.

Reductive decyanation of N-protected 6-Amino-3-azabicyclo[3.1.0]hexanecarbonitriles

Abstract The cyano moiety in dibenzylamino-3-azabicyclo[3.1.0]hexane-6-carbonitriles 14c,d can be removed reductively by alkali metals: sodium in liquid ammonia at low temperatures causes a reaction with retention of configuration whilst lithium in an ethylamine - ammonia mixture at 0°C leads predominantly to inversion of configuration. The analogous diallylamino species 14e is less suitable for reductive decyanation. It can be used, however, for the synthesis of a 3-azabicyclo[3.2.0]heptane diamine 22. The solid state conformation of an N(3)-unsubstituted 3-azabicyclohexane skeleton is determined by an X-ray structural analysis.

Spatially fixed oligoamines IV. 1 flexibility and protonation of meander-type octamines

Meander-type octamines 6a and 6b possessing three piperazine units, two bicyclo[3.1.0]hexyl- and two azabicyclo[3.1.0]hexyl systems as building blocks, could be obtained by reductive amination of di(oxobicyclohexyl)piperazine 2 with piperazinyl-3azabicyclohexane derivatives 5a/b, respectively. The latter were synthesized from Nbenzylchloroenamine 11 and sodium borohydride and subsequent removal of the benzylic protection group. Conformation and molecular flexibility of the new oligoamines 6a and 6b were studied. Di- and tetraammonium species with definite location of the protons were generated from octamine 6b. X-Ray structural analysis of diammonium salt 14 · 2 TFA was used to give an insight into the molecular arrangement of an (azoniabicyclohexyl)piperazine trifluoromethane sulfonate unit.

Functionalized chloroenamines in aminocyclopropane synthesis. IV: A synthesis for bicyclic lactams from carbamoylated chloroenamines ― The result of a tandem ring contraction-cyclization process

Abstract Reaction of N-tosylcarbamoylated chloroenamines 6b-d with sodium cyanide in acetonitrile gave [n.3.0] bicyclic lactams 8b-d instead of the expected [n.1.0] bicyclic compounds of type 7. X-ray structure analyses of 8b-d established an uniform cis-anellation of the pyrrolidone system and an uniform exo-position of the morpholino moiety. A similar formation of a lactam was observed upon the reaction of the carbamoylated chloroenamines 6b and 11 with sodium borohydride. In the case of 11 an endo-morpholino product 12 could be isolated which rearranged to the more stable exo-morpholino bicyclic system 13 upon heating. 6b directly provided the thermodynamically controlled exo-morpholino isomer 10. Using LiAlH4 as hydride reagent converted 6a-c into aminocyclopropanes 20a-c; the carbamoyl moiety, thereby, simultaneously was reduced to an aminomethyl group. A bicyclo [2.1.0]pentyl morpholine 20a, accessible by this method, isomerized into a cyclopentenyl morpholine 22 upon heating in the presence of acid. 8, 10, 12 and 13 could be regarded as subsequent product of primarily formed aminocyclopropane derivatives 2. A tandem ring contraction - cyclization process better seems to explain at least the formation of the [n.3.0] bicyclic lactams 8 from chloroenamines 6 and cyanide.

Functionalized chloroenamines in aminocyclopropane synthesis - V.1 synthesis and reactions of aminocyclopropylketones

Abstract Conjugated acylated chloroenamines 5A,C were available by chlorination of mixtures of acylated enamines 8A,C/9A,C by NCS at 0°C. Nonconjugated chloroenamines 10Aa and 10Ba could be obtained by NCS-chlorination of the conjugated acylenamines 9A,B at low temperature. Reaction of 5Aa-5Ac,5Ae, 5Af with cyanide produced morpholinocyclopropylketones 11A. In two cases aminofurans 12Ad and 12Ca resulted as products of this reaction. More generally amino-aryl-furans 12 were formed by thermolysis of the aryl-cyclopropyiketones 11. Amino-alkyl-furans as 12Ae and 12Af only could be trapped by a Diels-Alder reaction leading to 16Ae and 16Af. Epoxyenamines 29A,B unexpectedly were produced from the interaction of cyanide with the chloroenamines 10Aa and 10Ba.